AXIAL.EC Report Summary

Summary of the context and overall objectives of the project

The formation of a functional patterned vascular network is essential for development, tissue growth and organ physiology. Several human vascular disorders arise from the mis-patterning of blood vessels, such as arteriovenous malformations, aneurysms and diabetic retinopathy. Although blood flow is recognised as a stimulus for vascular patterning, very little is known about the molecular mechanisms that regulate endothelial cell behaviour in response to flow and promote vascular patterning. Recently, we uncovered that endothelial cells migrate extensively in the immature vascular network, and that endothelial cells polarise against the blood flow direction (Franco PLoS Biol 2015, Franco eLIFE 2016). AXIAL.EC project aims at investigating how this newly discovered vascular plasticity is regulated and its relationship to vascular malformations. Vascular malformations include arteriovenous malformations, low-flow venous malformations, cavernous malformations, and aneurysms, are all vascular anomalies that arise from maladaptive connectivity of vascular networks. Vascular malformations have a great impact on human health, but so far have very poorly defined etiologies. AXIAL.EC integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular adaptation and maladaptation in the context of vascular malformations. Identifying cellular and molecular mechanisms leading to formation, development, and regression of vascular malformations could lead to new clinical treatments.AXIAL.EC project aims at investigating how this newly discovered vascular plasticity is regulated and its relationship to vascular malformations. Vascular malformations include arteriovenous malformations, low-flow venous malformations, cavernous malformations, and aneurysms, are all vascular anomalies that arise from maladaptive connectivity of vascular networks.Vascular malformations have a great impact on human health, but so far have very poorly defined etiologies. Identifying cellular and molecular mechanisms leading to formation, development, and regression of vascular malformations could lead to new clinical treatments.AXIAL.EC project aims at understanding the dynamic behaviour of endothelial cells during vascular adaptation and maladaptation; controlling and restoring vascular adaptation by regulating flow-mediated polarisation of endothelial cells; identifying novel regulators of flow-dependent endothelial cell polarisation.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

Within the ERC project, we have established a novel reporter mouse line to observe and manipulate endothelial polarity in vivo (Aim1a; Barbacena, in preparation). We will now use this tool to investigate how polarisation and coordination of endothelial cells movements are orchestrated to generate vascular patterning (Aim1b-d). In addition, we have manipulated cell polarity using Pard3 and Prkci models, and found that Par polarity complex is important for flow-dependent polarisation and prevents atherosclerosis (Takao et al. EMBO rep. in 2nd revision). At the molecular level, we found that mechanotransduction at adherens junctions promotes VEGF-dependent and inhibits Flow-dependent collective polarity of endothelial cells (Carvalho et al. submitted; Cejudo et al. in preparation). All related to Aim2 and Aim3.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

AXIAL.EC integrative approach, based on high-resolution imaging and unique experimental models, will provide a unifying model defining the cellular and molecular principles involved in vascular adaptation and maladaptation in the context of vascular malformations. Identifying cellular and molecular mechanisms leading to formation, development, and regression of vascular malformations could lead to new clinical treatments.